Risk factors of catheter- associated bloodstream infection: Systematic review and meta-analysis

Introduction The prevalence of catheter-associated bloodstream infections (CLABSI) is high and is a severe health problem associated with an increase in mortality and elevated economic costs. There are discrepancies related to the risk factors of CLABSI since the results published are very heterogeneous and there is no synthesis in the description of all the predisposing factors. Objective We aimed to perform a systematic review and meta-analysis to synthesize and establish the risk factors predisposing to CLABSI reported in the literature. Method This is a systematic review of observational studies following the PRISMA recommendations. MEDLINE and CINAHL databases were searched for primary studies from 2007 to 2021. The protocol was registered in PROSPERO CRD42018083564. Results A total of 654 studies were identified, 23 of which were included in this systematic review. The meta-analysis included 17 studies and 9 risk factors were analyzed (total parenteral nutrition (TPN), chemotherapy, monolumen and bilumen catheters, days of catheterization, immunosuppression, kidney disease and diabetes mellitus) due to the homogeneity of their definitions and measurements. The risk factors found to increase the probability of developing CLABSI were TPN, multilumen devices, chemotherapy treatment, immunosuppression and the number of days of catheterization. On the other hand, monolumen devices presented a lower likelihood of triggering this infection.


Introduction
The use of central venous catheters (CVCs) has increased in current medical practice and is widely used in hospitalized patients [1,2]. Safe administration of different medications and use by nursing teams is ensured by advances in the technology of these devices and insertion techniques, among others. However, despite the multiple benefits, CVCs are also associated with (central line)-associated bloodstream infections (CLABSI) [3][4][5][6].
In the United States 80,000 episodes of CLABSI are diagnosed annually and are associated with increased mortality and elevated economic costs (39,000 US dollars per episode) [7]. Despite including CLABSI in the Bacteremia 0 program and in nosocomial infection surveillance programs in Catalonia (VINCAT) or the Study of the Prevalence of Nosocomial Infections in Spain (EPINE), the rates of CLABSI remain elevated in our country [8]. According to EPINE, 45.80% of nosocomial bacteremias are secondary to a vascular device, with central venous access devices and peripherally inserted central catheters (PICC) being the cause in 34.39% and 11.42% of the cases, respectively [1]. The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) reports that the rates of CLABSI range between 15% and 30% in Spain [3]. Other international studies have reported catheter-associated infection rates of 6.3% to 23% of all nosocomial bacteremias and others describe 15.2% [9,10]. Moreover, the high prevalence of this complication has led to it becoming one of the major causes of morbidity and mortality in hospitalized patients [5,11]. According to SEIMC, the direct mortality attributable to bacteremia is between 12% and 25% [3,12], with a repercussion on the health care system of a mean cost of 18,000 euros per episode, depending on the causative microorganism [13].
In addition to the high rates and severity of outcomes, many studies have described a multitude of risk factors. In 2007, one systematic review studied the risk of CLABSI based on the venous device implanted and the time in place [14]. However, this study did not evaluate other related risk factors that could increase the risk of CLABSI, such as those related to some treatments [4,5,15,16], pathological history [5,[17][18][19][20][21] and clinical status [5,18,20,22]. Thus, the results obtained in the different studies are very heterogeneous, and do not synthesize and identify all the factors that favor the appearance of CLABSI. Therefore, here we provide a systematic review and meta-analysis that synthesizes and establishes the risk factors predisposing central venous catheter-associated bacteremia described in the literature.

Design
In accordance with the prevailing guidelines, our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO, registration number CRD42018083564). This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [23].

Search strategy
We performed serial literature searches for articles published in MEDLINE (via PubMed) and CINAHL, from 2007 to February 25, 2021, using the following keywords: "CLABSI", "CRBSI" "Catheter" and "Risk factor". Boolean operators were used to enhance electronic searches. All human studies published in full-text form were eligible for inclusion, with no language restriction in the searches. Additional studies of interest were identified by hand searches of bibliographies of expert authors (Pittiruti, M and Maki, D) (S1 Text).

Study eligibility and selection criteria
Three authors (EL, AT and CE) independently determined study eligibility. Any difference in opinion regarding eligibility was resolved through consensus.
Studies were included if they: involved participants 18 years of age or older; mentioned the risk factors associated with central venous devices, whether centrally or peripherally inserted (CICC/PICC, respectively); definition of catheter-associated bacteremia according to the criteria of the Centers for Disease Control (CDC)/National Healthcare Safety Network (NHSN); studies published in the last 14 years; and the study design was randomized control trials, cohort or case-control studies. We excluded studies with patients not hospitalized during the whole study.

Definition of variables and outcomes
The primary outcome of this study was the presence of CLABSIs or (central line)-related bloodstream infection (CRBSI) in patients with CICC or PICC.
A CICC was defined as any central venous access device inserted into the internal jugular or subclavian vein. PICCs were defined as catheters inserted in the basilic, axillar, cephalic, or brachial veins of the upper extremities with tips terminating in the cavoatrial junction. CLABSI or CRBSI was defined as the occurrence of bacteremia in patients with PICCs or CICCs according to CDC /NHSN criteria [7]

Data abstraction and validity assessment
Data were extracted from the studies included with use of a standardized template designed by our group. The following information was collected from all studies: study characteristics (author, year of publication, country, study design and patient population), variables related to vascular access/device (vascular access device, CLABSI ratio), variables and potential risk factors evaluated in each study and results of multivariate analysis.

Study selection
All the studies containing abstracts and title were imported to Mendeley (version 1.19.3; Mendeley LDT, m Elsevier, London, United Kingdom). After excluding duplicate papers, three investigators (EL, AT and CE) independently screened the title and the abstract according to the inclusion and exclusion criteria. If the selection of the literature could be determined based on the criteria, the full text was further evaluated. Three investigators (EL, AT and CE) independently assessed the quality of the papers included. The grade of evidence and grade of recommendation were established according to the proposal of the Centre for Evidence-Based Medicine of Oxford [24]

Range of bias among the studies
The three authors (EL, AT and CE) independently evaluated the risk of bias.
To analyze the quality of potentially eligible articles the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) [25] statement for cohort, case and control studies was followed.

Inclusion in the meta-analysis, data extraction and statistical methods
A meta-analysis was performed using the most prevalent risk factors for the presence of CLABSI included in the quantitative review (total parenteral nutrition [TPN], number of lumens, days of catheter placement, chemotherapy, immunosuppression, kidney disease and diabetes).
For the data analysis in the case of days of catheterization, mean values and their standard deviations of each study were extracted and weighted mean differences and 95% confidence intervals (CI) were used. In the case of qualitative factors, odds ratios (OR) and 95% CI were calculated for each study. The Cochrane-Q test was performed to assess the degree of heterogeneity among studies, and the I2 index (Higgins et al. 2003) [26] was used to describe the percentage of variation across studies due to heterogeneity (I2 = 25%: low; I2 = 50%: moderate; I2 = 75%: high heterogeneity). Study-specific estimates were pooled using both the fixed effect model (Mantel-Haenzel-Peto test) and the random effect model (Dersimonian-Laird test). If significant heterogeneity was found, the random effect model results were shown. To the contrary, the fixed-effect model was presented. Forest Plots were created to describe the pooled analysis. Statistical significance was defined as a P value < 0.05. All of the statistical analyses were conducted using R Studio.
The sample size of the studies evaluated established the catheter as the unit of analysis. In the cohort follow-up studies, the sample size ranged between 115 and 85,849 catheters, except in one study [30], which did not report the number of catheters but described rates of days of catheter placement. The only case-control study evaluated [16] included a sample of 197 cases and 207 controls.

Quality of the studies included
Analysis of the quality of the studies included was performed according to the STROBE statement [25]. The quality of the studies included was 3a and 3b. Eighteen studies obtained a

PLOS ONE
Risk factors of catheter-associated bloodstream infection: Systematic review and meta-analysis grade 3a recommendation (78.26%) while 6 were 3b (21.74%). Of the latter 6 studies, one had a case-control design [16] and the 5 remaining studies [18,19,33,35,39] had a reduced sample size and did not achieve sufficient statistical power. Thus, the quality of the studies included in the review was good-regular.

Synthesis of the results
Among the 23 studies included, 17 were included in the meta-analysis [4, 15, 16-21, 28, 29, 33, 35-40]. The reasons for excluding six articles were: 1) the remaining risk factors were not defined or measured in the same way and did not allow for conclusive statistical tests, 2) they had not been analyzed in more than one study, and 3) the results of the studies did not show significance in the analyses performed. A total of 9 risk factors were identified and included in the meta-analysis due to the homogeneity of the definitions and measurements: administration of TPN, single, bilumen, or multilumen catheters (including trilumen, tetralumen and pentalumen catheters in the latter group), days of catheterization, chemotherapy, immunosuppression, kidney disease and diabetes mellitus.
3.6.2. This review has several limitations which are implicit in the studies included in the meta-analysis. Specifically, there was significant heterogeneity in the general results mainly derived from the data belonging to the risk factors of TPN, unilumen and bilumen catheters, days of catheterization, chemotherapy, kidney disease, diabetes and immunosuppression, which were attributed a high-moderate heterogeneity >25%. This heterogeneity could be related to the clinical diversity, sample size and variability of the results since they are very important variables which could explain the heterogeneity of the data as a whole. However, one of the variables studied presented a low heterogeneity < 25% (multilumen catheter) and, thus, may be attributed to very solid results with excellent homogeneity.

Discussion
The prevention of CLABSI is problematic, with severe clinical repercussions at an individual and organizational level, since the use of venous devices in the hospital setting is a transversal intervention that affects hospitalized, critical, and oncological patients alike. The different studies published show contradictory results and, therefore, the present review has focused on identifying and synthesizing the variables related to the appearance of CLABSI. The results indicate that TPN, multilumen devices, chemotherapy treatment, immune system compromise and the length of catheterization are risk factors for CLABSI. On the other hand, monolumen devices present a lower probability of triggering this infection.
Multiple studies established TPN as a risk factor of CLABSI. The guidelines of the American Society for Parenteral and Enteral Nutrition (ASPEN) and CDC relate TPN with the risk of CLABSI due to the preference of the microorganisms for dextrose [7,41]. However, ASPEN related other nutritional factors, such as a deficient nutritional status conditioning immune response to the risk of infection. Along the same line, another study corroborated that a state of malnutrition and hypoalbuminemia was associated with CLABSI (OR 3.13; 95% CI 1. 38-5.24, p<0.05) [42]. Other studies determined that the risk of CLABSI is dependent on the duration of catheterization and the length of TPN [43,44]. In addition, it has been shown that manipulation of venous devices and TPN by health care professionals may condition the appearance of CLABSI and should be manipulated with maximum precaution of sterile barriers [7]. Nonetheless, the studies included in this review coincide in establishing TPN as a risk factor, but it should be noted that one study [29] found no association between these two factors, perhaps secondary to the creation of a strategy of bundle manipulation/care/approaches that reduce the appearance of the problem. Therefore, the result of TPN as a risk factor should be interpreted with caution since the factors described could be factors independently related to CLABSI.
Chemotherapy has shown to be an independent factor of CLABSI, but as described in the literature, the cause of this association could be because of the vulnerability of developing any infectious process due to the neutropenia induced by cytostatic drugs [45,46]. In addition, this study shows that a state of immunosuppression is an independent factor of CLABSI due to immune system dysfunction [13,47,48]. However, the studies included in this review did not report whether the cause of the immunosuppression was secondary to a hematological disease, organ transplantation, autoimmune disease or acquired immunodeficiency, and thus, it is not possible to stratify the results based on the causative disease. On the other hand, the results of the meta-analysis identified immunosuppression as an independent risk factor, except in one study due to the reduced sample size [18].
In relation to the number of lumens of the venous devices, multilumen catheters were found to be an individual risk factor of CLABSI. These results coincide with the CDC recommendation (category IB) of implanting devices with the least number of lumens, since the microorganisms reach the catheter through the connections and with these devices the risk is higher due to the greater number of entries [7]. In addition, these devices are susceptible to greater manipulation, hindering adequate disinfection and device maintenance. However, multilumen catheters are indicated in patients with high pharmacologic requirements in whom it is not considered safe to reduce the number of lumens because of the risk of pharmacological interaction [49]. In these cases, the importance of the management and maintenance of these devices is important to note. Along this line, it has been demonstrated that the impregnation of lumens with antimicrobial substances reduces the risk of CLABSI [50].
The present review established that monolumen venous devices are a protective factor; however, a meta-analysis determined that there are no differences when high quality studies with homogeneous samples are analyzed [51]. Therefore, this contradiction among studies could also be related to the quality of management, care and adherence to guidelines by the professionals manipulating these devices [52].
In the case of days of catheterization, the studies included showed elevated heterogeneity in the results. Taking into account that the CDC has established that routine replacement of central devices is not necessary (category IB) [45], it seems that the real reason for the development of infection may be the deterioration and dysfunctionality which venous devices acquire by multiple manipulations over time. Previous studies have shown that the quality of catheter care and management is key in the colonization of these devices [52], with thrombosis and intraluminal and extraluminal fibrin favoring the growth of microorganisms [53].
Infection is the second cause of death in patients with kidney disease receiving hemodialysis therapy [54]. These patients live with precursor risk factors of CLABSI of different causes, such as immune compromise, being carriers of a vascular access for renal replacement therapies, resistance to antibiotics, comorbidities such as diabetes, and colonization by nasal Staphylococcus aureus which promote the risk of this infection [55]. However, there are discrepancies among the results obtained in the literature, and our study did not describe any association with catheter-related infection and kidney disease. This may be justified in that the concept of kidney disease is very wide, and all the patients with this disease present very different characteristics which may generate very heterogeneous and inconclusive results. In addition, the CDC states that correct manipulation of a vascular device and correct monitoring by professionals is the main intervention for the prevention of CLABSI [56]. This indicates that depending on the preventive measures applied at an institutional level, having kidney disease is a precursor risk factor for the development of CLABSI.
In our meta-analysis, diabetes was not determined to be an independent risk factor of CLABSI. However, in the literature a relationship has been described between this disease and compromise of immune response [57], which would explain the results of some studies which establish diabetes as a related factor [55]. The discordance of our results with others may be due to the fact that most of the studies included did not take into account the type of diabetes, the complexity of this disease, the treatment or the years of evolution, which could justify the heterogeneity in the results obtained.
In relation to the microbiological results, the most frequent microorganisms isolated were Gram-positive cocci, the most prevalent being coagulase-negative Staphylococci, thereby indicating a possible colonization by skin flora of the patient or secondary to manipulation of the device by different health care professionals. Other series of CLABSI in our setting showed the same trend [58,59]. However, one study performed in the United States described Enterobacter spp. and Candida spp. as the most prevalent and concluded that more evidence is necessary to establish why the patients are at risk of presenting CLABSI by these microorganisms to thereby develop preventive measures aimed at these microorganisms [60]. Despite the improvements implemented in recent years, the results demonstrate that studies should be focused not only on strategies of insertion but also on the management and maintenance of venous catheters.
The main limitation of this review is the long interval of time in the inclusion of the articles which may increase the heterogeneity of some of the variables (days of catheterization). Another limitation is that the quality of the studies was good-regular, despite not including any randomized study, and this did not allow the establishment of cause-effect relationship. One other limitation is that the quality of the maintenance of venous devices is a very important factor for the appearance of CLABSI, and its evaluation is difficult to measure and may induce overestimation of the effect of other variables of catheter-related infection. Another aspect to take into account is the elevated heterogeneity based on the variable analyzed. In addition, the large number of variables that can be analyzed as potential related factors are always subject to changes, modifications and extensions of risk factors predisposing to CLABSI, since there are other risk factors not considered in the articles included for analysis that may be related to the appearance of CLABSI. Finally, the last limitation is related to the microbiological results since we were unable to synthetize the results reported in these studies because some are described in real numbers while others are indicated in percentages, and some studies report the species and others the genus.
Despite these limitations, this review also has great strengths such as the meta-analysis which provided a synthesis of the results obtained to date and their clinical applicability.
Robust identification of risk factors may be useful for their inclusion in algorithms for deciding the most adequate venous device, in addition to the variables of pharmacotherapy and venous accesses available. It also allows including therapeutic strategies based on rigorous measures of asepsis with the aim of preventing and reducing the incidence of CLABSI, especially in patients with some of the present risk factors.

Conclusions
The decision to insert a venous device should be made based on individual evaluation of risk factors for the development of CLABSI since this complication can involve very severe clinical repercussions with very elevated health care costs. Well-designed studies with homogeneous patient samples are needed to increase the quality of the results and help evaluate the efficacy of these devices as well as the clinical benefits and profitability of the therapeutic strategies implemented.